Background: Hepatocellular carcinoma (HCC) represents 72% of liver cancers in Canada. In the phase III REFLECT trial, lenvatinib met the primary endpoint of non-inferiority in overall survival (OS) versus sorafenib and demonstrated superiority in secondary endpoints of progression free-survival (PFS), time to progression and objective response rate. Based on the REFLECT trial, lenvatinib has become the standard of care in the treatment of Canadian patients with unresectable HCC (uHCC). In the Phase III IMbrave150 trial, the use of the combination of atezolizumab and bevacizumab (atezo+bev) resulted in statistically significant improvement in OS and PFS versus sorafenib for patients with uHCC. The aim of this analysis was to estimate the cost-effectiveness of lenvatinib versus atezo+bev or sorafenib as first-line treatment for patients with uHCC from the perspective of Ministry of Health in Canada. Methods: A cost-utility analysis was conducted using a partitioned survival analysis. Health state membership for lenvatinib and sorafenib were estimated based on patient level data and clinical inputs from REFLECT and extrapolated using parametric survival models. Relative efficacy for atezo+bev was estimated from a de novo network meta-analysis. In the base-case analysis, estimates from REFLECT used in the NMA were adjusted for imbalances in baseline characteristics. Sensitivity analyses included the use of alternative approaches to determine relative efficacy. Health state utility values were determined with EQ-5D data collected in REFLECT. Drug acquisition costs were obtained from publicly available sources and medical resource utilization was based on a survey of Canadian clinicians. The time horizon was 10 years. Results of the incremental analysis were calculated sequentially. Results: In the base case lenvatinib was associated with cost savings of CAD$4,640 and CAD$120,095 and a QALY difference of 0.15 and -0.28 vs sorafenib and atezo+bev, respectively. The base case deterministic analysis resulted in lenvatinib being dominant over sorafenib and cost-effective vs. atezo+bev (sequential ICER for atezo+bev was CAD$425,754 per QALY). Results of the probabilistic sensitivity analysis (PSA) were consistent with the base case findings with lenvatinib being the optimal treatment strategy in >99% of iterations. Conclusions: Results of this analysis demonstrate that lenvatinib represents the optimal use of healthcare resources as a first-line treatment for uHCC in Canada.